Role of nicotinamide adenine dinucleotide phosphate-reduced oxidase proteins in pseudomonas aeruginosa-induced lung inflammation and permeability

Panfeng Fu, Vijay Mohan, Syed Mansoor, Chinnaswamy Tiruppathi, Ruxana T. Sadikot, Viswanathan Natarajan

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Earlier studies indicated a role for reactive oxygen species (ROS) in host defense against Pseudomonas aeruginosa infection. However, the role of nicotinamide adenine dinucleotide phosphate-reduced (NADPH) oxidase (NOX) proteins and the mechanism of activation forNADPH oxidase in P. aeruginosa infection are notwell-defined. Here, we investigated the role of NOX2 and NOX4 proteins in P. aeruginosa infection, ROS generation, and endothelial barrier function in murine lungs and in human lung microvascular endothelial cells (HLMVECs). Airway instillation of P. aeruginosa strain 103 (PA103) significantly increased ROS concentrations in bronchial alveolar lavage (BAL) fluid, along with the expression of NOX2 and NOX4, but not NOX1 and NOX3, in lung tissue. In addition, PA103-infected HLMVECs revealed elevated concentrations of ROS, NOX2, and NOX4. In murine lungs and HLMVECs, PA103 induced the NF-κB pathway, and its inhibition blocked PA103-dependent NOX2 and NOX4 expression. Barrier function analysis showed that heat-killed PA103 induced endothelial permeability in a dose-dependent manner, which was attenuated by treatment with small interfering (si) RNA specific for NOX4, but not NOX2. Furthermore, the knockdown ofNOX4, but notNOX2,with siRNAreduced PA103-mediated apoptosis inHLMVECs. In vivo, the down-regulation of NOX4 with NOX4 siRNA attenuated PA103-induced lung vascular permeability. The deletion of NOX2 in miceexerted no effect onpermeability, but offered significant resistance to P. aeruginosa-induced lung inflammation. These data show that P. aeruginosa lung infection up-regulates NOX2 and NOX4 expression and ROS generation,which play distinct roles in regulating lung inflammation, apoptosis, and permeability.

Original languageEnglish (US)
Pages (from-to)477-488
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume48
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

Keywords

  • Apoptosis
  • NADPH oxidase
  • Pseudomonas aeruginosa
  • Reactive oxygen species
  • Vascular permeability

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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